It has become increasingly common to treat a variety of medical conditions by introducing a medical device into the vascular system within a human. For example, medical devices used for the treatment of vascular disease include stents, stent-grafts, grafts, catheters, balloon catheters, guide wires, cannulas and the like.
In the case of a localized vascular disease, a systemic administration of a drug may not be desirable because the drug may have unwanted effects on parts of the body which are not to be treated, or because treatment of the diseased vasculature requires a high concentration of drug that may not be achievable by systemic administration. It is therefore often desirable to administer drugs in a localized manner to vascular tissues. Several devices for localized drug delivery are known, including a stent coated with an elutable drug, also known as a drug eluting stent (DES), and a balloon catheter coated with an elutable drug, also known as a drug eluting balloon (DEB).
DEBs and DESs are coated with a drug using a variety of coating techniques. When a drug-eluting device is inserted into a vascular organ, the drug may be slowly released into the surrounding vascular tissue, to provide a long lasting therapeutic effect. Alternatively, the drug may be rapidly released from the coating, with minimal drug remaining on the device shortly after implantation. Coatings with fast drug release characteristics are particularly advantageous if a medical device is not permanently implanted, as it is necessary in this situation to rapidly deliver drug to the vascular tissue at the time of treatment.
Non-stent based local delivery systems, such as DEBs, have also been effective in the treatment of vascular disease. Therapy commences when the DEB is inserted into the patient to a target site, and inflated at the target site, wherein the DEB is pressed against the vascular tissue to deliver the drug. When DEBs are used, it is advantageous for the drug in the coating to be retained on the balloon surface prior to inflation, and to be rapidly released and transferred to the vascular tissue upon inflation.
One of the potential drawbacks to the use of drug-eluting devices for the localized treatment of vascular disease, is the unintended release of drug away from the target site. This unintended release may occur during removal from the packaging and insertion into the body, tracking to and placement at the treatment site, during expansion or deployment of the device, or occur post-treatment as the device is withdrawn from the body. Such unintended release may result from physical dislodgement of the coating, drug diffusion, device contact with areas proximate the treatment site, or washing out of the drug from the surface of the device due to blood flow.
A drug commonly used for the localized treatment of vascular disease is paclitaxel. Paclitaxel can be coated onto a medical device using a variety of coating techniques. One technique involves combining the paclitaxel with an excipient, either in dry form using powder methods, or in solution or in suspension using solvent methods. The paclitaxel-excipient combination is then applied to the surface of the medical device, either in the form of a powder or via the application of the solution or suspension followed by a drying step.
There are numerous factors that must be considered when creating a paclitaxel-excipient combination, and when coating the combination onto a medical device. In general, combining drugs and excipients, and coating medical devices with drug-excipient combinations, are complicated areas of technology. They involve the usual formulation challenges, such as those of oral or injectable pharmaceuticals, together with the added challenge of maintaining drug adherence to the medical device until it reaches the target site and subsequently delivering the drug to the target tissues with the desired release and absorption kinetics.
A commercially available paclitaxel-eluting device which is currently marketed under brand name IN.PACT Admiral Drug-Coated Balloon by Medtronic is a balloon with a coating which is a formulation comprising paclitaxel and urea.
US2011/0295200 (Speck et al.) describes catheter balloons covered with paclitaxel in hydrated crystalline form or in hydrated solvated crystalline form, which are said to have immediate release and bioavailability of a therapeutically effective amount of paclitaxel at the site of intervention. In one embodiment, the catheter balloon is coated by dissolving paclitaxel in an aqueous solvent in the presence of urea, then completely or partially wetting the balloon surface with the solution, then letting the solvent evaporate. It is noted that in the presence of urea in the coating layer of paclitaxel on the balloon surface, release of the drug from the surface was promoted.
There is a need to develop further paclitaxel-containing coatings for use in the localized treatment of vascular disease. In particular, there is a need to develop coatings for medical devices comprising paclitaxel that can deliver therapeutically relevant levels of paclitaxel to a target vascular tissue, in a localised manner, on a suitable timescale. The coating should have good adherence to the medical device during device preparation, manipulation and insertion, while also having suitable release characteristics once in contact with the target vascular tissue. The paclitaxel, when formulated in the coating, should be stable to sterilization, in particular ethylene oxide sterilization. When the medical device has a coating with an additional therapeutic agent (i.e. other than paclitaxel), the paclitaxel-containing coating should be compatible with the additional therapeutic agent.